Abstract
The hotspots of structural polymorphisms and structural mutability in the human genome remain to be explained mechanistically. We examine associations of structural mutability with germline DNA methylation and with non-allelic homologous recombination (NAHR) mediated by low-copy repeats (LCRs). Combined evidence from four human sperm methylome maps, human genome evolution, structural polymorphisms in the human population, and previous genomic and disease studies consistently points to a strong association of germline hypomethylation and genomic instability. Specifically, methylation deserts, the ∼1% fraction of the human genome with the lowest methylation in the germline, show a tenfold enrichment for structural rearrangements that occurred in the human genome since the branching of chimpanzee and are highly enriched for fast-evolving loci that regulate tissue-specific gene expression. Analysis of copy number variants (CNVs) from 400 human samples identified using a custom-designed array comparative genomic hybridization (aCGH) chip, combined with publicly available structural variation data, indicates that association of structural mutability with germline hypomethylation is comparable in magnitude to the association of structural mutability with LCR–mediated NAHR. Moreover, rare CNVs occurring in the genomes of individuals diagnosed with schizophrenia, bipolar disorder, and developmental delay and de novo CNVs occurring in those diagnosed with autism are significantly more concentrated within hypomethylated regions. These findings suggest a new connection between the epigenome, selective mutability, evolution, and human disease.
Highlights
Array comparative genomic hybridization studies [1] and massively parallel sequencing [2] revealed that approximately 10% of the human genome is structurally polymorphic at the submicroscopic scale (,4 Mb), a much larger fraction than affected by single nucleotide polymorphisms (SNPs)
Because the Polycomb repressive complex 2 (PRC2) is known to regulate bivalent promoters, we examined the distribution of PRC2 binding regions within methylation deserts, focusing on the hyperconserved CpG domains (HCGDs) identified by Tanay et al [56]
We examined whether the methylation deserts are enriched for regions involved in regulation of tissue-specific gene expression using the set of 269 putative genomic regulatory blocks (GRBs) and their target genes identified in the human genome by Akalin et al [58]
Summary
Array comparative genomic hybridization (aCGH) studies [1] and massively parallel sequencing [2] revealed that approximately 10% of the human genome is structurally polymorphic at the submicroscopic scale (,4 Mb), a much larger fraction than affected by single nucleotide polymorphisms (SNPs). Structural mutations that occur in a number of well studied structurally unstable loci cause disease [3]. The discovery of these structurally mutable disease-associated loci gave rise to the concept of genomic disorders [3,4]. Their detailed analysis revealed the role of non-allelic homologous recombination (NAHR) and low copy repeats (LCR) in mediating recurrent deletions, duplications and inversions [5]. A potential role for LCR in inverted orientation has been elucidated recently for a specific type of complex duplication with an embedded triplicated segment in inverse orientation, DUP-TRP/INV-DUP [7]
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